11-87071621-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022918.4(TMEM135):c.362+6A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,611,004 control chromosomes in the GnomAD database, including 1,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (780 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (704 hom.)
• Consequence: TMEM135 NM_022918.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002120
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.332

Genes affected

TMEM135 (HGNC:26167): (transmembrane protein 135) Predicted to be involved in peroxisome organization. Predicted to act upstream of or within response to cold and response to food. Predicted to be located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-87071621-A-C is Benign according to our data. Variant chr11-87071621-A-C is described in ClinVar as [Benign]. Clinvar id is 3056691.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM135	NM_022918.4	c.362+6A>C		splice_donor_region_variant, intron_variant		ENST00000305494.6
TMEM135	NM_001168724.2	c.362+6A>C		splice_donor_region_variant, intron_variant
TMEM135	NR_033149.2	n.474+6A>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM135	ENST00000305494.6	c.362+6A>C		splice_donor_region_variant, intron_variant		1	NM_022918.4	P1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8510 AN: 151344 Hom.: 776 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.0485

GnomAD3 exomes AF: 0.0153 AC: 3821 AN: 249842 Hom.: 316 AF XY: 0.0117 AC XY: 1580 AN XY: 135314

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00653 AC: 9534 AN: 1459558 Hom.: 704 Cov.: 30 AF XY: 0.00579 AC XY: 4205 AN XY: 726120

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000547

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0563 AC: 8532 AN: 151446 Hom.: 780 Cov.: 32 AF XY: 0.0549 AC XY: 4062 AN XY: 73974

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.0480

Alfa AF: 0.0236 Hom.: 154

Bravo AF: 0.0645

Asia WGS AF: 0.0120 AC: 43 AN: 3474

EpiCase AF: 0.00202

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM135-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	7.5
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75455263; hg19: chr11-86782663;